Elevated FSH - A Driver for Sex Differences in Alzheimer's Disease

FSH 升高——阿尔茨海默病性别差异的驱动因素

基本信息

批准号：
10495197
负责人：
VAHRAM HAROUTUNIAN
金额：
$ 126.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10495197
关键词：
3xTg-AD mouse Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Amyloid beta-Protein Precursor Antibodies Architecture Area Asparagine Automobile Driving Blocking Antibodies Blood Body fat Brain Brain region Bypass Cells Cholesterol Clinical Cognitive Complement Coupled Data Dementia Discipline Disease Endocrinology Endopeptidases Energy Metabolism Estrogen Replacements Estrogens Evaluation Evolution Fatty acid glycerol esters Female Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Future Genetic study Goals Gonadal structure Health Hazards Hippocampus (Brain)Histocytochemistry Hormones Human Impaired cognition Injections Knock-in Mouse Life Longevity Maps Medical Menopause Mus Nature Neurofibrillary Tangles Neurons Neurosciences Obesity Organ Osteoporosis Ovariectomy Pathogenesis Pathway interactions Phase Phenotype Physiology Pituitary Hormones Postmenopause Proto-Oncogene Proteins c-akt Public Health Recombinant Follicle Stimulating Hormone Rodent Role Senile Plaques Serum Sex Differences Signal Transduction Small Interfering RNA Specific qualifier value Symptoms Technology Testing Textbooks Thyroid Gland Thyrotropin Transcript Treatment Protocols Up-Regulation Woman abeta accumulation aged base bone bone cell bone loss brain tissue cognitive function design disease phenotype endopeptidase A energy balance good laboratory practice hormonal signals hypercholesterolemia interdisciplinary collaboration knock-down laser capture microdissection loss of function male men mild cognitive impairment mouse model overexpression polyclonal antibody prevent receptor expression secretase small hairpin RNA tau Proteins transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) stands out as notable in two respects––in not having a cure and in affecting women more than men. While declining estrogen has been thought to underpin post–menopausal AD, there is a clear clinical correlation of AD with rising levels of follicle–stimulating hormone (FSH). Most notably, there is a ‘spike’ in cognitive decline in women in the early years of the menopausal transition, when serum estrogen is normal and FSH levels begin to rise. Collaborative studies between the Mount Sinai and Emory groups have identified FSH as a potential driver for AD—and suggest that rising FSH levels may contribute to the disproportionate increase of AD in aging women. Notably, we find that FSH receptors (FSHRs) are expressed in both mouse and human brain, and that the injection of recombinant FSH or ovariectomy (that elevates serum FSH) aggravates AD pathology and cognitive decline in 3xTg mice. Inhibiting the action of FSH in 3xTg or APP/PS1 mice by an FSH–blocking antibody or downregulating Fshr expression in the hippocampus prevents onset of the AD phenotype. The Emory group also provides strong preliminary evidence that FSH upregulates C/EBPβ, which activates asparagine endopeptidase (AEP), a δ–secretase that cleaves amyloid precursor protein (APP) and Tau––resulting in neuritic plaques and neurofibrillary tangles, respectively. The goal of the transdisciplinary collaboration between the disciplines of endocrinology and neuroscience is to fully understand the mechanism of FSH action on AD–vulnerable brain regions. Thus, in Specific Aim 1, we will map the distribution and cellular localization of the FSHR and its signaling partners CEBPB and LGMN in human and mouse brain using single–transcript technologies. In Specific Aim 2, we will examine the function of the brain FSHR in driving AD pathology and cognitive decline. For this, we will downregulate or overexpress the Fshr in specific brain areas of 3xTg mice by stereotaxically injecting AAV expressing siFshr or Fshr. We will also study the effect of high FSH in 3xTg mice rendered haploinsufficient in Cebpb, and delineate the transcriptomic architecture of FSH–treated human neuronal cells by RNA–seq. In Specific Aim 3, we will determine whether deleting the Fshr or inhibiting FSH action by our murine FSH blocking antibody, Hf2, injected over the lifespan of 3xTg mice can prevent the onset of cognitive decline. To contemporaneously replicate our data, the Emory group will study the effect of treating established cognitive impairment with Hf2 in 18–month–old APP knock–in (KI) mice. In all, our proof–of–concept studies––conducted using our Good Laboratory Practices (GLP) Platform––should not only establish a role for high FSH in driving AD, but also provide a framework for the future testing of our humanized FSH–blocking antibody, Hu6, in aging women.

项目概要阿尔茨海默病（AD）在两个方面引人注目——无法治愈以及影响虽然雌激素下降被认为是绝经后 AD 的主要原因，但实际上， AD 与卵泡刺激素 (FSH) 水平升高存在明显的临床相关性。在绝经过渡初期，当血清雌激素水平升高时，女性认知能力下降会出现“高峰” 西奈山和埃默里大学研究小组之间的合作研究表明，正常和 FSH 水平开始上升。确定 FSH 是 AD 的潜在驱动因素，并表明 FSH 水平升高可能会导致 AD 值得注意的是，我们发现 FSH 受体 (FSHR) 有所表达。在小鼠和人类大脑中，注射重组 FSH 或卵巢切除术（提高血清 FSH) 会加重 3xTg 小鼠的 AD 病理和认知能力下降抑制 3xTg 或 FSH 的作用。 APP/PS1 小鼠通过 FSH 阻断抗体或下调海马中的 Fshr 表达来预防埃默里大学研究小组还提供了 FSH 上调的有力初步证据。 C/EBPβ，激活天冬酰胺内肽酶 (AEP)，这是一种裂解淀粉样蛋白前体的 δ 分泌酶蛋白 (APP) 和 Tau——分别导致神经斑块和神经原纤维缠结。内分泌学和神经科学学科之间的跨学科合作旨在充分了解 FSH 对 AD 易受影响的大脑区域的作用机制，因此，在具体目标 1 中，我们将绘制人类 FSHR 及其信号伙伴 CEBPB 和 LGMN 的分布和细胞定位在具体目标 2 中，我们将检查使用单转录本技术的小鼠大脑的功能。大脑 FSHR 在驱动 AD 病理和认知能力下降中的作用为此，我们将下调或过度表达 FSHR。我们还将通过立体定向注射表达 siFshr 或 Fshr 的 AAV 在 3xTg 小鼠的特定大脑区域中进行 Fshr。研究高 FSH 对导致 Cebpb 单倍体不足的 3xTg 小鼠的影响，并描绘转录组通过 RNA-seq 分析 FSH 处理的人类神经元细胞的结构在特定目标 3 中，我们将确定是否通过在整个生命周期中注射我们的鼠 FSH 阻断抗体 Hf2 来删除 Fshr 或抑制 FSH 作用 3xTg 小鼠可以预防认知能力下降的发生。为了同时复制我们的数据，埃默里大学。该小组将研究在 18 个月大的 APP 敲入中使用 Hf2 治疗已确定的认知障碍的效果总之，我们的概念验证研究是使用我们的良好实验室规范 (GLP) 进行的。平台——不仅应该确立高FSH在驱动AD中的作用，还应该为未来提供一个框架在老年女性中测试我们的人源化 FSH 阻断抗体 Hu6。